Recently, problems related to a decreasing birthrate are frequently taken up, and various countermeasures have been tried in order to solve these problems. As countermeasures against a decreasing birthrate, it is obvious that it is important to give aid to couples who have no child due to infertility, while there is a strong request for developing effective treatments of infertility.
Infertility is caused at the same rate between men and women. However, because of the complexity of the mechanism of sperm formation, male infertility is not elucidated in many aspects, including its treatments, and there are unknown causes in many of the reproduction-associated problems, such as decreased number of human sperms and reduced reproductive potential. Although technical progress of In Vitro Fertilization (IVF) has become capable of conceiving and birthing also in cases of decreased activity of sperms, details of the molecular mechanism behind infertility still remain unclear, and there are many cases leading to difficulties in the selection of proper treatments and also to unsatisfactory therapeutic effects. For infertility therapy with fewer burdens, therefore, there is a strong request for developing genetic diagnoses and assisted reproductive technologies based on the understanding of the mechanism of infertility
According to Non Patent Literature 1, studies on male infertility in mice have demonstrated the existence of many genes which affect fertility. Mutations in these genes would be likely to contribute to causing male infertility also in humans.
As concerns morphological changes which are brought about after the meiosis during the process of sperm formation, on the other hand, it is reported that structural or functional changes specific to sperm cells are observed in enzymes utilized in energy metabolism. For example, there is observed activation of sperm-specific hexokinase (see, Non Patent Literature 2), phosphoglucoseisomerase (see, Non Patent Literature 3), aldolase (see, Non Patent Literature 4), glyceroaldehyde 3-phosphate dehydrogenase (see, Non Patent Literature 5), phosphoglycerate kinase (see, Non Patent Literature 6), phosphoglycerate mutase (see, Non Patent Literature 7), enolase (see, Non Patent Literature 8), and others. In Non Patent Literature 5, it is suggested that abnormalities in functions of these sperm-specific glycolytic enzymes is likely to be a cause of infertility, because (male) mice knocked-out for glyceroaldehyde 3-phosphate dehydrogenase are infertile and found to have poor motility of sperm.
Members of the family of phosphoglycerate mutases (PGAMs) in mice are encoded by two genes, Pgam-1 and Pgam-2, and form three isozymes, homo-PGAMs of type B and type M, and a hetero-PGAM. Although isozymes of these three types are detected in the testis of grown mice, type M isozyme is not identified in the testis of newborn mice and observed at 14 to 16 days after birth and later (see, Non Patent Document 9). It has been demonstrated that at the transcription level, type B is expressed strongly in the brain and kidney and moderately in the liver, thyroid gland, muscle, and heart, and type M strongly in the muscle and testis and moderately in the heart and lung (see, Non Patent Document 10). While expression analysis of PGAM in human testis has not been made, it has been found that PGAM1 (type B) is expressed in the liver and brain and PGAM2 (type M) in the muscle (see, Non Patent Document 11). In humans, it is known that as an isozyme of type B, PGAM4 containing no introns (PGAM3, PGAM-B) is present (see, Non Patent Document 12). Functioning of PGAM4 in the testis would be suggested, because PGAM of type M, in addition to type B, is thought to be expressed also in the human matured testis, while many of the genes expressed specifically in the testis do not contain introns (see, Non Patent Documents 13 and 14). Therefore, changes in the gene encoding PGAM4 may lead to abnormalities in PGAM functions in sperms. As a result, it would be likely that the energy supply via the glycolytic system is reduced and the motility of sperm is decreased, thereby resulting in impairments in fertilization